Insoluble polypeptide or protein microspheres containing therapeutic agents which enable the controlled release thereof in biological systems have generated growing interest in recent years [Kramer, J. Pharm. Sci., 63, page 1646 (1976); Widder et al: Cancer Research, 40, page 3512 (1980) and Widder et al; J. Pharm. Sci., 68, page 79 (1979)]. Systems utilizing the microspheres have the potential advantage of prolonging effective drug concentrations in the blood stream or tissue when injected thereby reducing the frequency of administration; localizing high drug concentrations; reducing drug toxicity, and enhancing drug stability. Albumin is a preferred protein or polypeptide for the preparation of such microspheres since it is a naturally occurring product in human serum. Although it is usually necessary to cross-link the albumin when preparing microspheres according to conventional methods cross-linked albumin may still be degraded depending upon cross link density thereby enabling the use thereof for drug delivery systems, etc.
Conventional methods for the preparation of albumin microspheres are generally of two types. In one method, aqueous dispersions of albumin are insolubilized in vegetable oil or isooctane or other hydrocarbon solvent by denaturing at elevated temperatures (110.degree.-165.degree. C.). Another method involves chemical cross-linking of the aqueous dispersion of albumin at room temperature. Typical of these two types of methods are those described in U.S. Pat. Nos. 4,147,767; 4,356,259; 4,349,530; 4,169,804; 4,230,687; 3,937,668; 3,137,631; 3,202,731; 3,429,827; 3,663,685, 3,663,686; 3,663,687; 3,758,678 and Ishizaka et al, J. Pharm. Sci., Vol. 20, page 358 (1981).
These methods, however, result in the formation of relatively hydrophobic microspheres which usually require a surfactant in order to disperse a sufficient quantity thereof in water or other systems for administration to a biological system to ensure the delivery thereto of an effective amount of any biologically active agent entrapped therein. In addition, the hydrophobic nature of conventional polypeptide microspheres make it extremely difficult to "load" large quantities of water soluble biologically active agents or other material within the microspheres after synthesis.
It is an object of the present invention to provide more hydrophilic polypeptide microspheres which will accept high "loadings" of biologically active substances or other materials especially by addition of such substances after microsphere synthesis, and to prepare such drug loaded microspheres which do not require the utilization of surfactants to enable the preparation of highly concentrated dispersions thereof.
It is a further object of the invention to provide hydrophilic microspheres which may be more readily modified by aqueous chemical methods to covalently attach proteins, enzymes, antibodies, immunostimulants, and other compounds to alter and improve microsphere properties.
It is a further object of the present invention to provide a novel method for the preparation of such hydrophilic microspheres.
It is still a further object of the present invention to provide novel hydrophilic microspheres containing biologically active or other substances and a method for the preparation thereof.
It is still a further object of the present invention to provide a composition for administration to an animal, including humans, comprising the novel hydrophilic polypeptide microspheres containing a biologically active substance.
It is still a further object of the present invention to provide a novel method for administering a biologically active substance to an animal based upon a system comprising hydrophilic polypeptide microspheres containing a biologically active substance.